Toxins are potent molecules used by bacteria, that can act locally or at a distance from the infection site in a host organism. While some toxins, cause disruption of all cell types (e.g. cytotoxins), other toxins are only active on specific cells such as enterotoxins active on epithelial intestinal cells and neurotoxins targeting neuronal cells. This specificity is achieved by the recognition of specific cell surface receptor(s) and/or specific intracellular target(s). The nervous system is one of the main targets of bacterial toxins. One of the most common bacterial neurotoxin is the botulinum neurotoxin (BoNT).
Botulinum neurotoxin (BoNT) is secreted by the bacterium Clostridium botulinum, and is one of the most toxic compounds known to man. The lethal dose for humans has been estimated to be as little as 1 nanogram per kilogram of body weight. Exposure to the toxin causes flaccid paralysis of cells resulting in muscle weakness, impaired respiratory function, malfunction of the nervous system and ultimately death by respiratory failure. The extreme potency of the neurotoxin presents a potential threat for use in bio-warfare; however, in small doses, BoNT has many medicinal and cosmetic benefits such as the treatment of neuromuscular disorders and prevention of wrinkles (e.g. Botox).
There are seven distinct isoforms of the toxin, designated as BoNT type-A (BoNT/A) through BoNT type-G (BoNT/G) that are produced by different strains of the botulinum bacterium, also designated types A-G, respectively. Each isoform has a similar function within cells, ultimately inhibiting neurotransmission through cleavage of one of the three SNARE proteins. BoNT/A, is the serotype most commonly used for therapeutic purposes. BoNT is secreted as a 150 kDa single polypeptide chain consisting of two units connected via a disulfide bond, designated the heavy chain (HC), which is about 100 kDa, and a light chain (LC), which is about 50 kDa. The mechanism of BoNT is highly complex and has been characterized. Upon entering the body, the toxin attacks nerve cells through a three step process. First, the HC binds to the bilayer membrane of a neuron forming a transmembrane protein pore. Second, the LC translocates the formed pore and is released into the cytosol. Third, the LC cleaves one of three SNARE proteins (SNAP-25, synaptobrevin, or syntaxin) prohibiting SNARE complex formation and subsequent acetylcholine release/neurotransmission, and thus muscular contraction.
Despite its extreme toxicity, BoNT/A has many therapeutic uses. Starting in 1980, BoNT/A was used to treat strabismus (“crossed eyes”) and blepharospasm (“uncontrollable blinking”). By 1989, the FDA had also approved the use of BoNT/A to treat hemifacial spasms (“uncontrollable spasms of facial muscles”). It was at this time that various studies of BoNT/A for treating facial wrinkles began. By 2002, the FDA had approved the use of BoNT/A for treating wrinkles around the eyes and mouth. In addition to these current uses, BoNT/A is currently approved for Upper Motor Neuron Diseases (e.g., amyotrophiclateral sclerosis, Lou Gehrig's disease and pseudobular palsy) and spasticity. Studies for treating hyperhidrosis (excessive sweating), migraines, asthma, and prostatic symptoms (i.e., abnormal prostate symptoms) using BoNT/A are currently underway.